Functional Analysis of SCN5A Genetic Variants Associated with Brugada Syndrome.

BACKGROUND: Brugada syndrome (BrS) is a rare inherited cardiac arrhythmia with increased risk of sudden cardiac death. Mutations in gene SCN5A, which encodes the α-subunit of cardiac voltage-gated sodium channel NaV1.5, have been identified in over 20% of patients with BrS. However, only a small fraction of NaV1.5 variants, which are associated with BrS, are characterized in electrophysiological experiments. RESULTS: Here we explored variants V281A and L1582P, which were found in our patients with BrS, and variants F543L and K1419E, which are reportedly associated with BrS. Heterologous expression of the variants in CHO-K1 cells and the Western blot analysis demonstrated that each variant appeared at the cell surface. We further measured sodium current in the whole-cell voltage clamp configuration. Variant F543L produced robust sodium current with a hyperpolarizing shift in the voltage dependence of steady-state fast inactivation. Other variants did not produce detectable sodium currents, indicating a complete loss of function. In a recent cryoEM structure of the hNaV1.5 channel, residues V281, K1419, and L1582 are in close contacts with residues whose mutations are reportedly associated with BrS, indicating functional importance of respective contacts. CONCLUSIONS: Our results support the notion that loss of function of NaV1.5 or decrease of the channel activity is involved in the pathogenesis of BrS.

Case Report: Loss-of-Function ABCC9 Genetic Variant Associated With Ventricular Fibrillation.

Genetic variants in the ABCC9 gene, encoding the SUR2 auxiliary subunit from KATP channels, were previously linked with various inherited diseases. This wide range of congenital disorders includes multisystem and cardiovascular pathologies. The gain-of-function mutations result in Cantu syndrome, acromegaloid facial appearance, hypertrichosis, and acromegaloid facial features. The loss-of-function mutations in the ABCC9 gene were associated with the Brugada syndrome, early repolarization syndrome, and dilated cardiomyopathy. Here, we reported a patient with a loss-of-function variant in the ABCC9 gene, identified by target high-throughput sequencing. The female proband presented with several episodes of ventricular fibrillation and hypokalemia upon emotional stress. This case sheds light on the consequences of KATP channel dysfunction in the cardiovascular system and underlines the complexity of the clinical presentation of ABCC9-related diseases.